The present invention relates to improved methods for the preparation of oligonucleotides and nucleoside phosphoramidites. More particularly, the methods utilize activators that have certain advantages over conventional activators used in the preparation of nucleoside phosphoramidites, and in their coupling to form oligomers. More specific objectives and advantages of the invention will hereinafter be made clear or become apparent to those skilled in the art during the course of explanation of preferred embodiments of the invention.
The study of oligonucleotides has become a key area of interest for many reasons including potential uses in therapeutic and diagnostic applications (Agrawal, S., TIBTECH, 1996, 14, 375-382; Marr, J., Drug Discovery Today, 1996, 1, 94-102; Rush, W., Science, 1997, 276, 1192-1193). One of the more interesting applications of oligonucleotides is the ability to modulate gene and protein function in a sequence specific manner. A direct result of studying oligonucleotides including their analogs in variety of applications is the need for large quantities of compounds having high purity. Presently, the synthesis of oligonucleotides and their analogs remains a tedious and costly process. There remains an ongoing need in this area for developing improved synthetic processes that facilitate the synthesis of oligonucleotides.
Phosphoramidites are important building blocks for the synthesis of oligonucleotides. The most commonly used process in oligonucleotide synthesis using solid phase chemistries is the phosphoramidite approach. In a similar process the support used is a soluble support (Bonora et al., Neucleic Acids Res., 1993, 21, 1213-1217). The phosphoramidite approach is also widely used in solution phase chemistries for oligonucleotide synthesis. Deoxyribo-nucleoside phosphoramidite derivatives (Becaucage et al., Tetrahedron Lett., 1981, 22, 1859-1862) have also been used in the synthesis of oligonucleotides.
Phosphoramidites for a variety of nucleosides are commercially available through a myriad of vendors. 3xe2x80x2-O-phosphoramidites are the most widely used amidites but the synthesis of oligonucleotides can involve the use of 5xe2x80x2-O-and 2xe2x80x2-O-phosphoramidites (Wagner et al., Neuclosides and Neuclotides, 1997, 17, 1657-1660; Bhan et al., Neuclosides and Neuclotides, 1997, 17, 1195-1199). There are also many phosphoramidites available that are not nucleosides (Cruachem Inc., Dulles, Va.; Clontech, Palo Alto, Calif.).
One of the steps in the phosphoramidite approach to oligonucleotide synthesis is the 3xe2x80x2-O-phosphitylation of 5xe2x80x2-O-protected nucleosides. Additionally, exocyclic amino groups and other functional groups present on nucleobase moieties are normally protected prior to phosphitylation. Traditionally phosphitylation of nucleosides is performed by treatment of the protected nucleosides with a phosphitylating reagent such as chloro-(2-cyanoethoxy)-N,N-diisopropylaminophosphine which is very reactive and does not require an activator or 2-cyanoethyl-N,N,Nxe2x80x2,Nxe2x80x2-tetraiso-propylphosphorodiamidite (bis amidite reagent) which requires an activator. After preparation the nucleoside 3xe2x80x2-O-phosphoramidite is coupled to a 5xe2x80x2-OH group of a nucleoside, nucleotide, oligonucleoside or oligonucleotide.
The activator most commonly used in phosphitylation reactions is 1H-tetrazole. There are inherent problems with the use of 1H-tetrazole, especially when performing larger scale syntheses. For example, 1H-tetrazole is known to be explosive. According to the material safety data sheet (MSDS) 1H-tetrazole (1H-tetrazole, 98%) can be harmful if inhaled, ingested or absorbed through the skin. The MSDS also states that 1H-tetrazole can explode if heated above its melting temperature of 155xc2x0 C. and may form very sensitive explosive metallic compounds. In addition, 1H-tetrazole is known to Hence 1H-tetrazole requires special handling during its storage, use, and disposal.
Aside from its toxicity and explosive nature 1H-tetrazole is acidic and can cause deblocking of the 5xe2x80x2-O-protecting group and can also cause depurination during the phosphitylation step of amidite synthesis (Krotz et al., Tetrahedron Lett., 1997, 38, 3875-3878). Inadvertent deblocking of the 5xe2x80x2-O-protecting group is also a problem when chloro-(2-cyanoethoxy)-N,N-diisopropylaminophosphine is used. Recently, trimethylchlorosilane has been used as an activator in the phosphitylation of 5xe2x80x2-O-DMT nucleosides with bis amidite reagent but this reagent is usually contaminated with HCl which leads to deprotection and formation of undesired products (Dabkowski, W., et al. Chem. Comm., 1997, 877). The results for this phosphitylation are comparable to those for 1H-tetrazole.
Activators with a higher pKa (i.e., less acidic) than 1H-tetrazole (pKa 4.9) such as 4,5-dicyanoimidazole (pKa 5.2) have been used in the phosphitylation of 5xe2x80x2-O-DMT thymidine (Vargeese, C., Neucleic Acids Res., 1998, 26, 1046-1050).
A variety of activators have been used in the coupling of phosphoramidites in addition to 1H-tetrazole. 5-Ethylthio-1H-tetrazole (Wincott, F., et al., Nucleic Acids Res. 1995, 23, 2677) and 5-(4-nitrophenyl)-1H-tetrazole (Pon, R. T., Tetrahedron Lett., 1987, 28, 3643) have been used for the coupling of sterically crowded ribonucleoside monomers e.g. for RNA-synthesis. The pKa""s for theses activators are 4.28 and 3.7 (1:1 ethanol:water), respectively. The use of pyridine hydrochloride/imidazole (pKa 5.23 (water)) as an activator for coupling of monomers was demonstrated by the synthesis of a dimer (Gryaznov, S. M., Letsinger, L. M., Neucleic Acids Res., 1992, 20, 1879). Benzimidazolium triflate (pKa 4.5 (1:1 ethanol:water)) (Hayakawa et al., J. Org. Chem., 1996, 61, 7996-7997) has been used as an activator for the synthesis of oligonucleotides having bulky or sterically crowded phosphorus protecting groups such as aryloxy groups. The use of imidazolium triflate (pKa 6.9 (water)) was demonstrated for the synthesis of a dimer in solution (Hayakawa, Y.; Kataoka, M., Nucleic Acids and Related Macromolecules: Synthesis, Structure, Function and Applications, Sep. 4-9, 1997, Ulm, Germany). The use of 4,5-dicyanoimidazole as an activator for the synthesis of nucleoside phosphoramidite and several 2xe2x80x2-modified oligonucleotides including phosphorothioates has also been reported (Vargeese, supra.).
Another disadvantage to using 1H-tetrazole is the cost of the reagent. The 1997 Aldrich Chemical Company catalog lists 1H-tetrazole at over ten dollars a gram for 98% material. The 99+% pure material lists for over forty seven dollars per gram. This reagent is used in excess of the stoichiometric amount of nucleoside present in the reaction mixture resulting in considerable cost especially during large scale syntheses.
The solubility of 1H-tetrazole is also a factor in the large scale synthesis of phosphoramidites, oligonucleotides and their analogs. The solubility of 1H-tetrazole is about 0.5 M in acetonitrile. This low solubility is a limiting factor on the volume of solvent that is necessary to run a phosphitylation reaction. An activator having higher solubility would be preferred to allow the use of minimum volumes of reactions thereby also lowering the cost and the production of waste effluents. Furthermore, commonly used 1H-tetrazole (0.45 M solution) for oligonucleotide synthesis precipitates 1H-tetrazole when the room-temperature drops below 20xc2x0 C. Thus, blocking the lines on the automated synthesizer.
Due to ongoing clinical demand (See, for example, Crooke et al., Biotechnology and Genetic Engineering Reviews, 1998, 15, 121-157) the synthesis of oligonucleotides and their analogs is being performed utilizing increasingly larger scale reactions than in the past. One of the most common processes used in the synthesis of these compounds utilizes phosphoramidites that are routinely prepared and used in conjunction with an activator. There exists a need for phosphitylation activators that poses less hazards, are less acidic, and less expensive than activating agents that are currently being used, such as 1H-tetrazole. This invention is directed to this, as well as other, important ends.
In one aspect, the present invention presents improved methods for preparing phosphitylated compounds comprising the steps of:
providing a compound having a hydroxyl group;
reacting said compound with a phosphitylating reagent in the presence of a pyridinium salt in a solvent under conditions of time, temperature and pressure effective to yield said phosphitylated compound.
In some preferred embodiments of the invention, the compound having a hydroxyl group is a nucleoside, preferably a 5xe2x80x2-protected nucleoside having a 3xe2x80x2-hydroxyl group. In further preferred embodiments, the compound is a nucleoside dimer having a 3xe2x80x2 or 5xe2x80x2-hydroxyl group. In still further preferred embodiments, said compound is a nucleoside having a 5xe2x80x2 or 2xe2x80x2 hydroxyl group.
In further preferred embodiments, the compound having a free hydroxyl group is an oligonucleotide or oligonucleotide analog having a 3xe2x80x2 or 5xe2x80x2 hydroxyl group.
In some preferred embodiments of the invention, the phosphitylating reagent is bis amidite reagent (2-cyanoethyl-N,N,Nxe2x80x2,Nxe2x80x2-tetraisopropylphosphorodiamidite), bis(N,N-diisopropylamino)-2-methyltrifluoroacetylamino-ethoxyphosphine or bis(N,N-diisopropylamino)-2-diphenyl-methylsilylethoxyphosphine.
In further preferred embodiments of the invention, the pyridinium salt is pyridinium hydrochloride, pyridinium trifluoroacetate or pyridinium dichloroacetate.
In further preferred embodiments of the invention, the solvent is dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran or a mixture thereof.
In further preferred embodiments, the activator is bound to a solid support. In Still further preferred embodiments, the activator is a polyvinyl pyridinium salt.
In a further aspect, the present invention provides improved methods for the preparation of intersugar linkages. In preferred embodiments, the methods of the invention are used in the preparation of oligonucleotides via standard solid phase oligonucleotide regimes.
In some preferred embodiments, the present invention presents methods for the preparation of a compound of Formula I: 
wherein:
R1 is a mononucleoside or an oligonucleotide;
R2 is a nucleoside linked to a solid support, or an oligonucleotide linked to a solid support;
Pg is a phosphorus protecting group; comprising:
providing a phosphoramidite of Formula II: 
wherein R6 is xe2x80x94N(R7)2 wherein R7 is alkyl having from one to about six carbons; or R7 is a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
and reacting said phosphoramidite with a hydroxyl group of a nucleoside linked to a solid support, or an oligonucleotide linked to a solid support;
said reaction being performed in the presence of an activating reagent, said activating reagent comprising at least one pyridinium salt and at least one substituted imidazole.
Also provided in accordance with the present invention are methods for the preparation of an oligonucleotide comprising the steps of:
providing a 3xe2x80x2-mononucleoside phosphoramidite or 3xe2x80x2-oligonucleotide phosphoramidite; and
reacting said 3xe2x80x2-mononucleoside phosphoramidite or 3xe2x80x2-oligonucleotide phosphoramidite with the 5xe2x80x2-hydroxyl of a nucleoside, nucleotide, or oligonucleotide in the presence of an activating reagent;
said activating reagent comprising at least one pyridinium salt and at least one substituted imidazole.
In some preferred embodiments, the 3xe2x80x2-mononucleoside phosphoramidite or oligonucleotide phosphoramidite is reacted with the 5xe2x80x2-hydroxyl of a solid-support bound nucleoside, nucleotide or oligonucleotide.
In further preferred embodiments of the foregoing methods of the invention, the oligonucleotide comprises phosphorothioate intersugar linkages.
The present invention also provides synthetic methods comprising: providing a phosphoramidite of Formula II: 
xe2x80x83wherein
R1 is a mononucleoside or an oligonucleotide;
Pg is a phosphorus protecting group;
R6 is xe2x80x94N(R7)2 wherein R7 is alkyl having from one to about six carbons; or R7 is a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen; and
reacting said phosphoramidite with a hydroxyl group of a nucleoside linked to a solid support, or an oligonucleotide linked to a solid support, to form a compound of Formula I: 
said reaction being performed in the presence of an activating reagent, said activating reagent comprising at least one pyridinium salt and at least one substituted imidazole; and
oxidizing or sulfurizing said compound to form a compound of Formula III: 
wherein Q is O or S, with S being preferred.
In some preferred embodiments of the forgoing methods, the substituted imidazole is 1-methylimidazole.
In further preferred embodiments of the foregoing methods, the pyridinium salt has the formula 
where Xxe2x88x92 is trifluoroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, xe2x88x92O-trifluorosulfonyl, hexafluorophosphate or tetrafluoroborate, with trifluoroacetate being preferred.
In a further aspect of the invention, synthetic methods are provided comprising:
providing a compound of Formula X: 
xe2x80x83wherein:
B is a nucleobase;
R8 is H, a hydroxyl protecting group, or a linker connected to a solid support;
W is an optionally protected internucleoside linkage;
q is 0 to about 50;
R4 is H, F, Oxe2x80x94R, Sxe2x80x94R or Nxe2x80x94R (R10);
R is H, a protecting group, or has one of the formulas: 
xe2x80x83where
each m is independently from 1 to 10;
y is from 0 to 10;
E is H, a hydroxyl protecting group, C1-C10 alkyl, N(R10)(R11) or Nxe2x95x90C(R10)(R11); substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, wherein the substitutions are selected from one or several halogen, cyano, carboxy, hydroxy, nitro and mercapto residues;
each R10 or R11 is, independently, H, substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, wherein the substitutions are selected from one or several halogen, cyano, carboxy, hydroxy, nitro and mercapto residues; alkylthioalkyl, a nitrogen protecting group, or R10 and R11, together, are a nitrogen protecting group or wherein R10 and R11 are joined in a ring structure that can include at least one heteroatom selected from N and O;
or R is xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94N(R10)(R11);
reacting the compound of Formula X in the presence of an activating reagent with a compound of Formula XI: 
where r is 0 to about 50;
R5 is a hydroxyl protecting group;
R6 is xe2x80x94N(R7)2 wherein R7 is alkyl having from one to about six carbons; or R7 is a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
to form a compound of Formula XII: 
wherein said activating reagent comprises at least one pyridinium salt and one substituted imidazole.
In some preferred embodiments, the pyridinium salt has the formula: 
where Xxe2x88x92 is trifluoroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, xe2x88x92O-trifluorosulfonyl, hexafluorophosphate, or tetrafluoroborate, with trifluoroacetate being preferred.
In further preferred embodiments, the substituted imidazole is 1-methylimidazole.
In some preferred embodiments, R8 is a linker connected to a solid support.
In further preferred embodiments, R4 is xe2x80x94Oxe2x80x94R wherein R has the formula xe2x80x94[xe2x80x94(CH2)mxe2x80x94Oxe2x80x94]yxe2x80x94E; m is 2, y is 1; and E is CH3, xe2x80x94N(R10)(R11), or xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R10)(R11).
In further preferred embodiments, r is 0. In still further preferred embodiments, R6 is diisopropylamino.
Preferably, Pg is xe2x80x94CH2CH2CN, xe2x80x94CH2CHxe2x95x90CHCH2CN, para-CH2C6H4CH2CN, xe2x80x94(CH2)2-5N(H)COCF3, xe2x80x94CH2CH2Si(C6H5)2CH3, or xe2x80x94CH2CH2N(CH3)COCF3. with xe2x80x94CH2CH2CN being more preferred.
Some preferred embodiment of the methods further comprising oxidizing or sulfurizing the compound of Formula XII to form a compound of Formula XIII: 
where Q is O or S, with S being preferred.
Some further preferred embodiments of the methods further comprising a capping step, which is preferably performed prior to oxidation.
Some further preferred embodiments further comprising the step of cleaving the oligomeric compound to produce a further compound of formula X.
In a further aspect of the invention, methods are provided for the preparation of internucleoside linkages between nucleosides having 2xe2x80x2-substituents, using an activating reagent that is preferably an imidazolium triflate. In some preferred embodiments, these methods comprise:
providing a compound of Formula X: 
xe2x80x83wherein:
B is a nucleobase;
R8 is H, a hydroxyl protecting group, or a linker connected to a solid support;
W is an optionally protected internucleoside linkage;
q is 0 to about 50;
R4 is H, F, Oxe2x80x94R, Sxe2x80x94R or Nxe2x80x94R(R10);
R is H, a protecting group, or has one of the formulas: 
xe2x80x83where
each m is independently from 1 to 10;
y is from 0 to 10;
E is H, a hydroxyl protecting group, C1-C10 alkyl, N(R10)(R11) or Nxe2x95x90C(R10)(R11); substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, wherein the substitutions are selected from one or several halogen, cyano, carboxy, hydroxy, nitro and mercapto residues; and
each R10 or R11 is, independently, H, substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-Cl0 alkynyl, wherein the substitutions are selected from one or several halogen, cyano, carboxy, hydroxy, nitro and mercapto residues; alkylthioalkyl, a nitrogen protecting group, or R10 and R11, together, are a nitrogen protecting group or wherein R10 and R11, are joined in a ring structure that can include at least one heteroatom selected from N and O;
or R is xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94N(R10)(R11);
provided that R14 is not H or OH;
reacting the compound of Formula X in the presence of an activator with a compound of Formula XI: 
where r is 0 to about 50;
R5 is a hydroxyl protecting group;
R6 is xe2x80x94N(R7)2 wherein R7 is alkyl having from one to about six carbons; or R7 is a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen; to form a compound of Formula XII: 
xe2x80x83wherein the activator has the formula G+Uxe2x88x92, where
G+ is selected from the group consisting of pyridinium, imidazolium, and benzimidazolium; and
Uxe2x88x92 is selected from the group consisting of hexafluorophosphate, tetrafluoroborate, triflate, hydrochloride, trifluoroacetate, dichloroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, and xe2x88x92O-trifluorosulfonyl.
Preferably, the activator is imidazolium triflate.
In some preferred embodiments, R8 is a linker connected to a solid support. In further preferred embodiments, R4 is is xe2x80x94Oxe2x80x94R wherein R has the formula xe2x80x94[xe2x80x94(CH2)mxe2x80x94Oxe2x80x94]yxe2x80x94E; m is 2, y is 1; and E is CH3, xe2x80x94N(R10)(R11), or xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R10)(R11).
In further preferred embodiments, r is 0. In still further preferred embodiments, R6 is diisopropylamino.
Preferably, Pg is xe2x80x94CH2CH2CN, xe2x80x94CH2CHxe2x95x90CHCH2CN, paraxe2x80x94CH2C6H4CH2CN, xe2x80x94(CH2)2-5N(H)COCF3, xe2x80x94CH2CH2Si(C6H5)2CH3, or xe2x80x94CH2CH2N(CH3)COCF3. with xe2x80x94CH2CH2CN being more preferred.
Some further preferred embodiments further comprise oxidizing or sulfurizing the compound of Formula XII to form a compound of Formula XIII: 
where Q is O or S, with S being preferred.
Some further preferred embodiments of the methods further comprising a capping step, which is preferably performed prior to oxidation.
Some further preferred embodiments further comprising the step of cleaving the oligomeric compound to produce a further compound of formula X.
In a further aspect of the invention, synthetic methods are provided comprising:
providing a compound of Formula XX: 
xe2x80x83wherein:
R4 is H, F, Oxe2x80x94R, Sxe2x80x94R or Nxe2x80x94R (R10);
R is H, a protecting group, or has one of the formulas: 
xe2x80x83where
each m is independently from 1 to 10;
y is from 0 to 10;
E is H, a hydroxyl protecting group, C1-C10 alkyl, N(R10)(R11) or Nxe2x95x90C (R10)(R11); substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, wherein the substitutions are selected from one or several halogen, cyano, carboxy, hydroxy, nitro and mercapto residues; and
each R10 or R11 is, independently, H, substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, wherein the substitutions are selected from one or several halogen, cyano, carboxy, hydroxy, nitro and mercapto residues; alkylthioalkyl, a nitrogen protecting group, or R and R10, together, are a nitrogen protecting group or wherein R and R2 are joined in a ring structure that can include at least one heteroatom selected from N and O;
or R is xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94N(R10)(R11);
R5 is a hydroxyl protecting group;
Z1 is aryl having 6 to about 14 carbon atoms or alkyl having from one to about six carbon atoms;
Y1 is O or S;
Y2 is O or S;
Y3 is C(xe2x95x90O) or S;
v is 2 to about 4;
B is a nucleobase;
R6 is xe2x80x94N(R7)2 wherein R7 is alkyl having from one to about six carbons; or R7 is a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;
reacting said compound of Formula XX with a compound of Formula XXI: 
xe2x80x83wherein:
R8 is H, a hydroxyl protecting group, or a linker connected to a solid support;
in the presence of an activator to form a compound of Formula XXII: 
xe2x80x83wherein the activator has the formula G+Uxe2x88x92, where
Gxe2x88x92 is selected from the group consisting of pyridinium, imidazolium, and benzimidazolium; and
Uxe2x88x92 is selected from the group consisting of hexafluorophosphate, tetrafluoroborate, triflate, hydrochloride, trifluoroacetate, dichloroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, and xe2x88x92O-trifluorosulfonyl;
or said activator is a substituted imidazolium triflate.
Preferably, the activator is imidazolium triflate.
In some preferred embodiments, v is 2; and Y3 is C(xe2x95x90O). In further preferred embodiments, Z is methyl, phenyl or t-butyl, with t-butyl being preferred.
In some preferred embodiments, n is 0. In further preferred embodiments, R8 is a linker to a solid support.
In some preferred embodiments, Y1 and Y2 are each O. I other preferred embodiments, Y1 and Y2 are each S. In still further preferred embodiments, Y1 is O and Y2 is S.
Preferably, each R7 is isopropyl.
In some preferred embodiments, n is 0; R3 is H, R6 is diisopropylamino; Y1 is O; Y2 is S; and Z is methyl or t-butyl, with t-butyl being preferred.
In some preferred embodiments of each of the foregoing methods, each constituent nucleobase xe2x80x9cBxe2x80x9d is devoid of exocyclic amine protection.
Preferably, W is an optionally protected phosphodiester, phosphorothioate, phosphorodithioate, or alkyl phosphonate internucleotide linkage.
Some preferred embodiments of the foregoing methods further comprise oxidizing or sulfurizing the compounds of Formula XXII to form a compound of Formula XXIII: 
where Q is O or S.
Some further preferred embodiments of the methods further comprising a capping step, which is preferably performed prior to oxidation.
Some further preferred embodiments further comprising the step of cleaving the oligomeric compound to produce a further compound of formula XXI.
In-some preferred embodiments, G+ is pyridinium and Uxe2x88x92 is hexafluorophosphate or tetrafluoroborate, with hexafouoroborate being preferred.
In further preferred embodiments, G+ is imidazolium or benzimidazolium and Uxe2x88x92 is selected from the group consisting of triflate, hydrochloride, trifluoroacetate, dichloroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, and xe2x88x92O-trifluorosulfonyl.
In other preferred embodiments, G+ is imidazolium or benzimidazolium and Uxe2x88x92 is selected from the group consisting of hexafluorophosphate, tetrafluoroborate, and triflate.
In further preferred embodiments, G+ is imidazolium or benzimidazolium and Uxe2x88x92 is selected from the group consisting of hydrochloride, trifluoroacetate, dichloroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, and xe2x88x92O-trifluorosulfonyl.
In still further preferred embodiments, G+ is imidazolium and Uxe2x88x92 is selected from the group consisting of hexafluorophosphate, tetrafluoroborate, triflate, hydrochloride, trifluoroacetate, dichloroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, and xe2x88x92O-trifluorosulfonyl.
In still further preferred embodiments, Uxe2x88x92 is selected from the group consisting of hexafluorophosphate, tetrafluoroborate, and triflate.
In further preferred embodiments, Uxe2x88x92 is selected from the group consisting of hydrochloride, trifluoroacetate, dichloroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, and xe2x88x92O-trifluorosulfonyl.
In further preferred embodiments, G+ is benzimidazolium and Uxe2x88x92 is selected from the group consisting of hexafluorophosphate, tetrafluoroborate, triflate, hydrochloride, trifluoroacetate, dichloroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, and xe2x88x92O-trifluorosulfonyl.
In further preferred embodiments, G+ is benzimidazolium and Uxe2x88x92 is hexafluorophosphate, tetrafluoroborate, or triflate.
In further preferred embodiments, G+ is benzimidazolium and Uxe2x88x92 is selected from the group consisting of hydrochloride, trifluoroacetate, dichloroacetate, xe2x88x92O-mesyl, xe2x88x92O-tosyl, xe2x88x92Br, and xe2x88x92O-trifluorosulfonyl.
In some prefered embodiments, the activator is substituted or unsubstituted imidazolium triflate, with unsubstituted imidazolium triflate being preferred.